Administration of cancer chemotherapeutic agents including cisplatin induces nausea and vomiting in nearly all cases. Vomiting begins to occur 1 to 2 hours after administration of cisplatin, which is acute vomiting, and vomiting begins to subside by 18 to 24 hours. Then, vomiting begins to develop and peaks 48 to 71 hours, which is delayed vomiting.
Further, nausea and vomiting are the most common complications occurring after anesthesia and surgery. Postoperative vomiting may cause severe complications such as dehydration, electrolyte imbalance, gastric herniation, wound disruption, esophageal tears, muscular fatigue, etc., and it may increase anxiety about additional surgery in patients. In general, postoperative vomiting occurs within 24 hours after surgery in 25 to 40% of surgical patients.
Meanwhile, vomiting may be treated by antagonistic action of 5-HT3 (5-hydroxytryptamine) receptor antagonist at the cerebral functions related to 5-HT3 receptors.
The first-generation 5-HT3 receptor antagonist, ondansetron or granisetron is very effective for acute vomiting, but less effective in preventing delayed vomiting. Therefore, ondansetron or granisetron must be given intravenously once or more times before chemotherapy or radiotherapy is initiated. Thereafter, it must be given orally in a tablet or elixir form in order to prevent delayed vomiting. Because some anticancer chemotherapeutic agents can induce vomiting for a predetermined period of time or longer even when they are administered only once, a 5-HT3 antagonist must be administered every day until the risk of vomiting has substantially subsided.
U.S. Pat. No. 5,202,333 discloses an intravenous formulation of tricyclic 5-HT3 receptor antagonists including a bridged bicyclic amine substituent, such as palonosetron. This document discloses that an administration dose of the tricyclic 5-HT3 receptor antagonist generally ranges from 1 ng to 1 mg, preferably 10 to 100,000 ng per 1 kg of body weight. This document discloses a composition consisting of palonosetron hydrochloride, dextrose monohydrate, citric acid monohydrate, sodium hydroxide, and water for injection, but there is a problem that pharmaceutically acceptable storage stability was not secured.
Palonosetron hydrochloride is marketed under the brand name of ALOXI®. This product is a liquid formulation for single intravenous administration, available as a 5 mL single use vial or a 1.5 mL single use vial. Each 5 mL vial contains 0.25 mg of palonosetron, 207.5 mg of mannitol, citrate buffer, and disodium edetate. Each 1.5 mL vial contains 0.075 mg of palonosetron, 83 mg of mannitol, citrate buffer, and disodium edetate.
Korean Patent Nos. 10-1113084 and 10-1113087 disclose a pharmaceutically stable composition at pH of 4 to 6, including palonosetron, mannitol, citrate buffer, and 0.005 to 1.0 mg/ml of EDTA (ethylenediaminetetraacetic acid) as a chelating agent. In these documents, to secure stability of the pharmaceutically composition including palonosetron, disodium edetate or EDTA is used as a chelating agent. EDTA is used to treat acute and chronic lead poisoning by removing toxic elements including heavy metals such as lead, cadmium, and mercury from the blood stream (chelation therapy). EDTA chelation therapy is approved by the U.S. FDA for use in treating lead and heavy metal poisoning, and also used for emergency treatment of hypercalcemia and control of ventricular arrhythmias associated with digitalis toxicity. However, the most common side effect of EDTA is a burning sensation at the site of the injection, and some people may have an allergic reaction to EDTA. Other serious side effects that have been reported include low blood sugar, diminished calcium levels, headache, nausea, low blood pressure, kidney failure, organ damage, irregular heartbeat, seizures, or even death.
For pharmaceutically effective application of compositions including palonosetron, stability of palonosetron must be improved to secure a pharmaceutically available period. Therefore, a demand for a palonosetron formulation with pharmaceutically effective storage stability still remains.